Polymorph and Salt/Cocrystal Screening to Identify a Suitable Physical Form for an LPAR1 Antagonist, GS-2278

Abstract

GS-2278 (1), a novel freebase lysophosphatidic acid receptor 1 (LPAR1) antagonist, was selected as a development candidate for the treatment of idiopathic pulmonary fibrosis (IPF). Investigations on this active pharmaceutical ingredient (API) resulted in the discovery of 15 crystalline forms, of which the unsolvated form 1-A was initially selected as the development form over the hemihydrate 1-1/2H₂O due to superior physical properties, including its unsolvated nature, simple thermal profile, and hygroscopicity profile. However, due to low solubility in simulated physiological fluids (∼10 μg/mL) and poor pharmacokinetics (30× lower than a nonprecipitating solution), investigations into acidic salts and cocrystals (∼50 coformers) were conducted to identify an acceptable physical form for long-term development. While no crystalline cocrystals were identified, several crystalline salts were identified, including an HCl salt, of which the dihydrate (1-HCl 2H₂O) was extensively characterized to mitigate potential challenges of its hydrated status. Ultimately, it was found to be nonhygroscopic, to have an acceptable pharmacokinetics profile (comparable to the nonprecipitating solution), robustness toward milling, compression, and drying, as well as physical/chemical stability in the drug product tablet. Because of this, a process was designed whereby 1-A and 1-HCl 2H₂O were selected as the penultimate and drug substance forms, respectively.